How Free Radicals Destroy the Brain & How Glutathione Can Help

In this article, I will be explaining to you what is a free radical, their connection to mitochondria & DNA damage, how they are the main contributors to cardiovascular disease, their heavy-influence on cognitive function, and more.

So free radicals really sound like a bad thing. But the thing with human beings, and many other organisms, is that we need a little bit of hardship in order to thrive. For example, if you stop exercising, you will become weaker and unhealthier. Your body won’t develop properly, and you will suffer a decline in cognitive performance.

But isn’t this contradictory? Exercise is a stressful activity that causes you to experience increased oxidative stress, which is an increase in the exposure to free radicals.

The answer is no. In moderation, in the right amounts, and in the right context, free radicals can be beneficial to our health by stimulating an adaptive response (hormesis) and to serve anticancer & anti-pathogenic biological functions. In fact, chemotherapy partly works by bombarding cancer cells with free radicals.

But the answer is also yes. It is shown that extreme bouts of physical exertion, like running a marathon, may actually negatively affect the immune system and the production of glutathione- our body’s master antioxidant.

So free radicals isn’t all that it seems to be at face value. Let’s take a closer look by first defining what a free radical is.

What is a Free Radical?

oxygen free radical diagram example — By Healthvalue [CC BY-SA 3.0], via Wikimedia Commons Notice the missing electron on the outer orbital of the oxygen atom.

A free radical, or radical for short, is an atom or a group of atoms that have one or more unpaired electrons. Unpaired refers to an electron that occupies an orbital of an atom all by itself, rather than being a part of an electron pair (two electrons in the same orbital with opposite spin). An unpaired electron is quite reactive because they want to become stable by grabbing other electrons to fill out their outer energy level.

So generally speaking, paired electrons are quite stable, whereas unpaired electrons are quite reactive.

The reactivity of unpaired electrons is what makes free radicals able to damage cellular structures and DNA. Although most of the time, the free radicals are controlled by the body as a part of a normal biological function. For example, the immune system uses free radicals to destroy pathogens. And the electron transport chain transfers lone electrons from electron donors to acceptors as a normal function of the mitochondria in aerobic respiration^[1].

What is an Oxygen Radical?

A Reactive Oxygen Species (ROS) refers to any free radical that contains oxygen atom- an oxygen radical in other words.

Oxygen has two unpaired electrons in separate orbitals in its outer shell. This electronic structure makes oxygen especially susceptible to radical formation.

Usually when oxygen is reduced, or given extra electrons, it leads to the formation of ROS like peroxides (like hydrogen peroxide), superoxides, hydroxyl radicals, and singlet oxygen.

Sources of Reactive Oxygen Species

Oxygen derived free radicals are always being made (and depending on the context, required) in our body, given that we human beings mainly rely on an aerobic metabolism in order to function. One of the places that Reactive Oxygen Species (ROS) is formed as a by product is in the mitochondria, as the mitochondria’s Electron Transport Chain uses & specifically reduces oxygen to produce H₂O in order to generate ATP.

Another instance that ROS is formed is by white blood cells. One type of white blood cell called neutrophils specialize (that’s their “job”) in the production of oxygen free radicals. Neutrophils defend our body by using ROS to kill invading pathogens.

Also, an environment may be a source of free radicals, or trigger the production of free radicals for cells. For example, cells experience an increase in ROS with hypoxia (a lack of sufficient oxygen) and hyperoxia (too much oxygen). A natural way that our cells experience hypoxia is during exercise.

Even our brain experiences a certain amount of hypoxia depending on the intensity of the exercise. But scientists don’t observe that exercise damages the brain overall. In fact, exercise increases brain neurogenesis and synaptic plasticity^[2], improves learning and memory^[3], and stops the age-related loss of brain tissue during aging while at the same time improving our ability to focus and process information quickly^[4].

Exercise makes us smarter- or at least makes our brain run better, even if exercise exposes our brain cells to a lack of oxygen. That’s because exercise-induced hypoxia causes an adaptive response by the brain to combat the free radicals generated by hypoxia. The same goes for the rest of our body.

3D model of Noopept — Noopept may improve brain function through stimulating an adaptive response to hypoxia- without the hypoxia.

Interestingly, there is a nootropic called noopept that signals to the brain that it is under a hypoxic condition, making the brain respond with adaptive measures artificially. In this way, noopept can also stimulates the growth & development of brain cells.

My point is that free radicals (controlled & in moderation) isn’t all bad. Our bodies are designed to deal with free radicals that are bound to be generated in an aerobic metabolism.

Another environmental trigger for free radical generation is ionizing radiation, which is any type of particle or electromagnetic wave that carries enough energy to “ionize” or remove electrons from an atom. Note that the ionizing radiation is more damaging to body tissues that is more oxygenated than deficient in oxygen. It makes sense, given that oxygen is the primary source of free radical generation in the body.

And of course, many different drugs, chemicals, environmental toxins, bad gut flora, etc. are sources of free radicals.

Mitochondria & Free Radical Generation

The mitochondria can be thought of as “the powerhouse of the cell”, due to their function of producing energy for the cell to use. Mitochondria has many energy-related processes going on inside it, like the energy-releasing activity of electron transport, proton pumps that stores energy in the form of an electrochemical gradient, and oxidative phosphorylation that allows your cells to utilize glucose & oxygen for the production of ATP.

Electron Transport Chain Free Radicals

Schematic diagram of the mitochondrial electron transport chain. — The electron transport chain in the mitochondrion is the site of oxidative phosphorylation in eukaryotes. The NADH and succinate generated in the citric acid cycle are oxidized, providing energy to power ATP synthase.

So what does mitochondria have to do with free radicals? Well, an essential structure of the mitochondria called the Electron Transport Chain (ETC) may occasionally leak free radicals. Specifically, when the mitochondria’s Electron Transport Chain is dealing with oxygen, a by product that may be produced is the anion radical superoxide (0₂^–).

Superoxide may further dismutate, which is when oxidized and reduced forms of a chemical species are produced simultaneously, to form hydrogen peroxide (H₂O₂).

H₂O₂ can further react to form the hydroxyl radical (HO). Note that that a hydroxyl radical is the neutral form of a hydroxide ion (OH^–).

Do note that Superoxide, hydrogen peroxide, and hydroxyl radicals are all free radicals that may damage our cell structures and DNA. So you can see that there is a serious cascade of free radicals that are generated as a result of mitochondrial cellular respiration, which emphasizes the importance of antioxidants to neutralize free radicals from doing damage.

Indeed there are safeguards that are built into our cells to suppress damage from free radicals; for example, our cells produce an enzyme called superoxide dismutase that neutralizes the superoxide free radical.

Monoamine Oxidase Free Radicals

magical brain patterns mind thoughts, cool brain patterns — Although excessive MAOI inhibition is probably a bad idea, mild MAOI inhibition may actually benefit the brain & body. Although I must say that MAOI is what makes coffee more so delicious, and cigarette smoking more so addictive.

In addition to the toxic radicals produced from the Electron Transport Chain reactions located at the inner mitochondrial membrane, the mitochondrial outer membrane’s enzyme monoamine oxidase catalyzes (speeds up) the oxidative deamination of biogenic amines (break down of amine neurotransmitters, such as dopamine, norepinephrine, epinephrine, histamine, and serotonin– not necessarily a bad thing) and is responsible for producing a large quantity of H2O2, contributing to the concentrations of reactive species inside both the mitochondrial matrix and cytosol (aqueous part of the cytoplasm of a cell)^[1].

How Free Radicals Damage Our Body

The good…

Free radicals can be good or bad, depending on the context. For example, free radicals are used by white blood cells to kill pathogens. And free radicals may also kill off cancerous cells in the right context.

Additionally, cultured cells exposed to free radicals such as superoxide and hydrogen peroxide stimulates the rate of DNA replication and cell proliferation- in this context, free radicals act as mitogens.

But why does this happen? Obviously free radicals damage cellular structures. I believe the benefit is due to hormesis, or an adaptive response by the cells. When the cells detect an increase in the amount of free radicals, the cells respond with an increased rate of mitosis (cell division) in order to compensate for the damaged cells that eventually die off.

From this example, you can see that free radicals are involved in cellular signaling- which is basically telling a cell what to do. I do believe this is also known as redox signaling.

The bad…

However, let me remind you that free radicals are molecules that have an unpaired electron that makes them highly reactive, and thereby able to damage macromolecules such as lipids, proteins, and nucleic acids.

For example, a well known toxic effect of free radicals is lipid peroxidation, which is the when free radicals damage cell membranes by “stealing” their electrons. The cell structure that is commonly vulnerable to lipid peroxidation are the (poly-) unsaturated fatty acids present in a cell’s phospholipid membrane.

Diagram depicting lipid peroxidation — Diagram showing the chain reaction in lipid peroxidation that a hydroxyl free radical sets off when reacting with a unsaturated fatty acid

In order to understand lipid peroxidation, you have to know that reactions involving radicals occur in chain reactions. For lipid peroxidation, a hydrogen is taken out from the fatty acid by a hydroxyl radical, leaving a carbon-centered radical as part of the fatty acid. That radical then reacts with oxygen to yield a peroxy radical, which can then react with other fatty acids or proteins.

Lipid peroxidation is not a good thing. Peroxidation of the lipid membranes causes an increase in a cell membrane’s rigidity, decreases the function of membrane-bound enzymes (i.e. sodium pumps), alters the function of membrane receptors, and changes the permeability of the membrane.

In addition to effects on phospholipids, radicals can also directly attack membrane proteins and induce lipid-lipid, lipid-protein and protein-protein crosslinking, all of which obviously have negative effects on membrane function^[5].

diagram showing atherosclerosis and its cross sections — By Npatchett (Own work) [CC BY-SA 4.0], via Wikimedia Commons Atherosclerosis is the disease process in which an artery wall thickens and narrows the space for blood to flow. Atherosclerosis happens as a result of invasion and accumulation of white blood cells (foam cells) and proliferation of intimal-smooth-muscle cell creating an atheromatous (fibrofatty) plaque. Note that when a blood vessel becomes narrower due to a pathology, this is called “stenosis”.

Through lipid peroxidation, free radicals are also the main cause of atherosclerotic cardiovascular disease. Which is a disease of the blood-transportation system due to arteries hardening and experiencing stenosis- another word for blood vessel becoming thicker and narrower such that blood flow becomes reduced. Free radicals may also damage cell DNA and mitochondrial DNA (mtDNA). Although cell DNA is a lot more stable to free radical damage, mtDNA is extremely vulnerable to free radical damage due to mtDNA only having 1 strand.

And of course, damage to cellular DNA can lead to cancer. And damage to mtDNA also promotes the incidence of atherosclerosis in the first place^[6].

How Do Free Radicals Affect Cognition?

So the next question is, how does oxidative stress affect our cognitive function? Again, it depends on the context.

Exposing the brain to increased levels of free radicals for a short duration (acute oxidative stress) can have an overall positive effect. A good example is exercise.

The free radicals produced through exercise can have positive effects on cognition by eliciting an adaptive response (hormesis).

Acute Oxidative Stress Increases Cell Division

One reason that comes to mind for the beneficial effect of acute oxidative stress is that free radicals are mitogens, as I’ve mentioned before. That may be one of the reasons why exercise is shown to increase the rate of cell division in the brain, neurogenesis (formation of new neurons), and angiogenesis (formation of new blood vessels). As a result, improvements in memory, attention, information processing speed, and executive function are all improved. Exercise also helps stave off dementia in the elderly^[7].

Acute Oxidative Stress Increases Active Glutathione

Acute exposure to oxidative stress through exercise is also shown to increases the baseline GSH glutathione levels in the body and in the brain^[8]. GSH is the active form of glutathione that protects cells from being damaged by free radicals. A lack of GSH levels (and other antioxidants) in the brain can be extremely detrimental to our cognition.

Understand that our cells wouldn’t be able to survive without glutathione. It is the body’s main antioxidant that allows us to survive the ROS burden of an aerobic metabolism.

Chronically High ROS Exposure Damages Brain Function

So what happens when you have deficient levels of glutathione and other antioxidants? Well, a lack of glutathione & other antioxidants means that your cells are exposed to higher levels of free radicals, perhaps over a long period of time depending on the context. This is a problem because your cells need antioxidants in order to survive ROS exposure.

Connection Between Chronically High ROS, Autism, and Dementia

Take for instance autistic children, whose brains do not develop properly. If you take a closer look, you’ll see that their mitochondria have decreased function, they have lower levels of GSH glutathione, and their cells are chronically exposed to higher than normal levels of free radicals^[9].

Note that a decrease in mitochondrial functions means a decrease in ATP production, the fuel that runs the cell. And with less ATP, the cells don’t function normally. Also, chronic exposure to increased levels of ROS damages and kills cells such that the harms outweigh the benefits (i.e. hormesis, mitogenic effect).

My conjecture is that a decrease in mitochondrial function may indicate that the mitochondria is working less in order to avoid being exposed to oxygen radicals that are produced while making ATP. Which may also indicate that there is a deficiency in GSH glutatione and other antioxidants to protect from free radicals generated through cellular respiration.

So a decrease in mitochondrial function and an increased cell apoptosis in the brain may explain the reduced cognitive function of autistic children. And if these problems are onset later in life, then it is perhaps what causes dementia.

It could be that autism and dementia are the same disease, except that the timing of the onset is different. And it makes more sense if you take into consideration that the body produces less glutathione the older you get.

And this all goes to show that there is an immense importance in our body’s antioxidant defense system. A deficiency in this system is likely to results in a decline in brain function.

So improving our antioxidant defense may actually be a way to improve our cognition.

Other Sources of Chronic Oxidative Stress

Notice that I’ve already mentioned that a chronic increase in ROS is harmful to the brain. Indeed, acute vs chronic elevations in ROS have different affects on the body & the brain. And uses up the GSH glutathione that we have in our body.

I already mentioned that acute oxidative stress can improve the human body & brain by stimulating our cell’s antioxidant defense. But chronic oxidative stress slowly destroys both the body & brain.

I’ve talked about chronic oxidative stress before in a previous article. Chronic stress accumulates free radical damage to our body & brain cells overtime, resulting in illnesses such as cancer & cardiovascular disease, contributing to diabetes, and reducing the function of the brain- sometimes to the extent of dementia.

If you have every experienced chronic stress, I bet you can even tell that I am on to something.

In a more relatable example, some people constantly suffer from emotional stress, office work, and being stuck in a noisy traffic jam when they go to work. Also, many people are sedentary- staying in one place for long periods of time. This is another a source of oxidative stress^[10][11].

When the stressor is not abated, you’ll start to notice that you have brain fog, that it is harder to remember & analyze information, that your body starts to become insulin resistant, that you heal slower, that you start to gain weight, and that you start to get depressed a lot more easily.

This all can be caused by chronically elevated (oxidative) stress. And that’s perhaps why a herb known as bacopa monnieri is known to improve memory by reducing stress.

Note that even exercise to the extreme extent falls in the category of being a source of chronic oxidative stress. For example, it is observed that running marathons can cause lower immune function^[12] and lower levels of GSH active glutathione levels^[13].

So it is of utmost importance to avoid situation of chronic stress in our day to day lives.

But what if you can’t escape (immediately) chronically stressful situations? Well there are still options available, other than exercise.

Supplements & Nootropics for Reducing ROS Exposure for Improved Cognition

Finally, in this section I will be talking about nootropics & supplements that improves brain function by reducing levels of ROS and improving the body’s antioxidant capacity.

Two places to start is to reduce excess inflammation in the body without compromising the immune system, and to lower stress levels. I’ve already mentioned bacopa for managing stress. There are also many herbs that lower inflammation, like ginger, lion’s mane & turmeric. Usually, I would have a thin slice of ginger after my meal for this purpose.

Noopept & Hypoxia

Interestingly, noopept works by activating the Hypoxia Inducible Factor 1 (HIF-1) DNA transcription factor^[14]. That means noopept works by tricking brain cells into reacting as if they were in an oxygen-deficient situation. But noopept doesn’t actually decrease the level of oxygen in the brain. So what happens is that your brain acquires the adaptive benefits of hypoxia-induced acute free radical exposure, without the free radicals and oxygen deficiency.

The result is that noopept may be able to restore cognitive function in Alzheimer Disease patients, lower ROS levels, and lower inflammation^[15].

N-acetylcysteine & Autism

Another promising nootropic for protecting the brain from high levels of free radicals is N-acetylcysteine. N-acetylcysteine is a precursor to glutathione, and supplementation of N-acetylcysteine is thought to aid in the production of glutathione. Indeed, the cysteine provided through this supplement is the rate limiting molecule for the production of GSH glutathione.

In one case study, an Iranian autistic child was given 800 mg per day of N-acetylcysteine (NAC) and the results were astonishing. Much of the child’s autistic behavior decreased within a period of two months^[16].

His social interaction with other children increased & his social impairment decreased. His verbal skills and communications improved. His aggression decreased significantly. His hyperactiveness & inattentiveness decreased. His limited interests started expanding. And his nail-biting behavior also significantly decreased.

The alleviation of his autistic symptoms all point to an improvement in cognitive function.

NAC works by increasing the production of active GSH glutathione in the body. And the patients who take NAC see a marked decline in inflammation & neuroinflammation, oxidative stress, and a reduction in high glutamate levels.

Frankincense & Dementia

Boswellia Serrata huge chunks of resin — Boswellia Serrata Frankincense that is commonly produced from India- Rich in boswellic acid, as well as rich in α-thujene

And finally one of my favorite nootropics is known as frankincense, specifically the Boswellia Carterii species, is shown to improve GSH glutathione levels^[17]; reduce lipid peroxidation, inflammation^[18], levels of ROS; fight back cognitive impairment like dementia & Alzheimer, and thereby improve memory & learning. Frankincense also has a range of benefits for the whole body, having anti-cancer^[19], anti-ulcer, anti-asthma, anti-arthritis, and anti- chronic pain properties^[20].

Again, the same trend is seen. Substances that reduce ROS & inflammation, and increase GSH improves our brain function.

Frankincense is also shown to inhibit acetylcholinesterase, an enzyme that breaks down acteylcholine^[17]. Acetylcholine is important for learning and memory formation, and increasing levels of the acetylcholine neurotransmitter is the way that nicotine works to improved cognitive function.

I also have personal experience with using both the essential oil and the resinous gum of boswellia carterii. I find both are effective, although perhaps the gum more so probably because less active constituents are left behind in the distillation process of making an essential oil. The administration method that I use is to topically apply the essential oil on my skin, and to chew on the frankincense resin.

I find that the effectiveness of the essential oil may depend on the brand that you buy from. I believe this is due to the fact that the manufacturer may choose to use different distillation methods. For example, the Now Foods Pure Frankincense Essential Oil has little to no psychoactive affect for me. It could still be effective for enhancing cognition, but immediate benefits are little to none in my experience. I believe this is because they use a distillation method called “folding”, which is to distill the essential oil once, and then redistill the extraction for a higher purity. But this may mean that much of the active constituents are lost in the distillation.

In comparison, I’ve found that Eden’s Garden Frankincense Boswellia Carterii Essential Oil to be a lot more psychoactive. I believe it is a lot less refined, which is good for an essential oil because more of the active ingredients are passed along. When using Eden’s Garden Frankincense oil, I find that I am a lot calmer & composed, and that I have increased mental clarity & focus.

But notice that one of the main active constituent of frankincense is boswellic acid (interestingly, you can find boswellic acid as a supplement too if you don’t want to chew/eat the tree gum). Apparently, boswellic acid isn’t normally extracted through steam distillation^[21][22], so you will be missing its benefits if you choose to use the essential oil.

There is a lot of research that I want to do on frankincense, but I will save it for another article in order to keep to the scope of this one.